The challenges of defining and managing treatment‐resistant depression in research and practice
Authors: Maurizio Fava
Journal: World Psychiatry (2023)

McIntyre et al1, in their excellent paper appearing in this issue of the journal, successfully tackle a critical issue in the field of depression: how should we define treatment-resistant depression (TRD) and how can we best manage it? They point out that a consensus definition of TRD with demonstrated predictive utility in terms of clinical decision-making and health outcomes does not currently exist, and that the definition adopted by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) – i.e., failure to respond to two or more antidepressant regimens despite adequate dose and duration and adherence to treatment – remains at the moment the reference one. Although it makes perfect sense that regulatory agencies rely on a definition which can be easily adopted in clinical trials, as it captures a large population with unmet needs, should researchers and clinicians routinely use the same approach? The Massachusetts General Hospital Staging Model (MGH-S) provides an example of a definition of TRD which integrates the number of failed trials with the intensity/optimization of each trial, without assuming a hierarchy of antidepressant classes2. An observational study of patients receiving antidepressant therapy (N=78,477)3 applied this model to claims data from the MarketScan Research Databases over a 24-month time period. Annual costs for patients with mild TRD (MGH-S score: 3.5-4) were 1,530$ higher than those for non-TRD patients, and annual costs for patients with complex TRD (MGH-S score ≥6.5) were 4,425$ higher than those for non-TRD patients (all p<0.001). A 1-point increase in the MGH-S score was associated with a 590$ increase in annual costs (p<0.001). There is, therefore, a clinical utility in adopting a staging method to evaluate the cost-effectiveness of new treatments for TRD. The MGH-S model has been recently updated to reflect some of the new treatments for TRD, including ketamine/esketamine, transcranial magnetic stimulation (TMS) and vagus nerve stimulation. The new version of the model4 provides a score for the characteristics of depression (including severity of the episode, presence or not of psychotic features, presence of suicidal ideation, and presence of anxious distress) (maximum score = 10), and a score for treatment history, considering the number of medication trials, the number of augmentation treatment trials, and the use of the above-mentioned new treatments as well as of electroconvulsive therapy (ECT) (maximum score = 25). We look forward to a wider adoption of this model in research and advanced clinical settings. As pointed out by McIntyre et al, intravenous ketamine and intranasal esketamine (co-administered with an antidepressant) have an established efficacy in the management of TRD, while some second-generation antipsychotics are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine-fluoxetine combination has established efficacy in FDA-defined TRD. However, despite the current FDA indication, the results of a pooled analysis5 suggest that adjunctive aripiprazole can be an effective intervention for patients whose symptoms worsen during antidepressant monotherapy, challenging the view that its benefits are limited to partial responders to antidepressants. The same may be true for other second-generation antipsychotics, supporting the need for further investigations. On the other hand, the authors highlight that ECT is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting its superiority over acute intravenous ketamine. The adoption of ECT in clinical practice, however, remains somewhat limited by the complexity of its administration and the possible adverse events. The authors also argue that manual-based psychotherapies are not established as efficacious on their own in TRD, although offering significant symptomatic relief when added to conventional antidepressants. Nevertheless, the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial compared the effectiveness of cognitive therapy and pharmacotherapy as second-step strategies for outpatients with major depressive disorder (MDD) who had received inadequate benefit from an initial trial of citalopram6. Among participants who were assigned to second-step treatment, those who received cognitive therapy had similar response and remission rates to those assigned to medication strategies, suggesting that there may be a role for cognitive therapy in TRD. The recent approval for the treatment of MDD of the combination of dextromethorphan (an uncompetitive N-methyl-D-aspartate receptor antagonist and sigma-1 receptor agonist) and bupropion (a norepinephrine-dopamine reuptake inhibitor), as well as the recent FDA filing of a new drug application for the GABAergic modulator zuranolone, raise the possibility that the scenario concerning medications available for MDD will change significantly in the near future. A large number of other novel compounds developed with non-monoamine molecular targets are currently in phase 2 or 3, again questioning whether clinicians in the next few years will continue to routinely use monoamine-based therapies in the initial algorithm for the treatment of depression. The current construct of TRD, focusing on the lack of response to what have been considered the first- or second-line monoamine-based treatments for MDD, may consequently become obsolete. Regardless of the methodology used to assess TRD patients, it is absolutely critical to carefully select subjects for randomization in clinical trials. "Professional patients" or duplicate subjects are a common problem in TRD trials, and may threaten the integrity of these studies. A number of digital platforms have been developed to identify duplicate subjects and allow investigators to exclude them from trials, as well as new methodologies to better document the treatment history of patients, including the measurement of blood levels of the ongoing therapies. To avoid the issues of diagnostic misclassification and severity of illness grade inflation, it is essential to ensure that patients enrolled for TRD trials really fulfill the needed requirements. Patients recruited in these trials may present with a heterogeneous group of symptoms representing several syndromes or subtypes, subsumed under the same diagnosis in the DSM-5 classification system. The SAFER interview7 has been developed to delineate a more symptom-specific and ecologically valid approach to the identification of the appropriate patients for MDD clinical trials through an independent assessment. It has been reported8 that, overall, 15.3% of MDD patients who had been deemed eligible at research sites were not eligible after the structured interview, with the most common reason being that patients did not meet the study requirements for level of treatment resistance. In MDD trials utilizing the SAFER interview as a tool to confirm eligibility, placebo response rates ranged between 13.0% and 27.3%, below the 30% to 40% average in antidepressant clinical trials, suggesting a benefit of the quality assurance provided by this interview. This reminds us of the importance to make sure that the right patients get into our TRD trials. In conclusion, there are currently several challenges in the definition and management of TRD, and the most significant feature of McIntyre et al's paper is probably its ability to reflect this evolving scenario.